7-aryl and heteroaryl ethers of desacetylforskolin

ABSTRACT

Novel forskolin derivatives, intermediates and processes for the preparation thereof, and methods for treating cardiac failure and memory deficit utilizing compounds or compositions thereof are disclosed.

This application is a division of application Ser. No. 295,840, filedJan. 11, 1989 now U.S. Pat. No. 4,999,351.

The present invention relates to forskolin derivatives. Moreparticularly, the present invention relates to 7-aryl and heteroarylethers of desacetylforskolin and derivatives of formula I ##STR1##wherein R₁ is hydrogen, loweralkyl, arylloweralkyl, a group of formulaR₃ R₄ R₅ Si, a group of formula R₈ CO, or a group of formula R₁₀ R₁₁N(CHR₁₂)_(n) CO wherein n is 0 or 1;

R₆ is hydrogen, a group of formula R₁₃ CO or a group of formula R₁₄ R₁₅NCO;

R₇ is phenyl, naphthyl, furanyl, oxazolyl, thiazolyl, pyridinyl,pyrimidinyl, purinyl, quinolinyl, or isoquinolinyl, each of which isunsubstituted or mono- or poly-substituted by loweralkyl, halogen ornitro;

R₉ is hydrogen; or

R₁ and R₉ taken together form a group of formula CO, a group of formulaSO or a group of formula CHNR₁₇ R₁₈ ;

R₃, R₄ and R₅ are the same or not all the same and each is hydrogen orloweralkyl;

R₈ is hydrogen or loweralkyl;

R₁₀, R₁₁ and R₁₂ are the same or not all the same and each is hydrogen,loweralkyl or arylloweralkyl; or

R₁₀ and R₁₁ taken together with the nitrogen atom to which they areattached form a group of formula ##STR2## wherein X is CO, O, S, a groupof the formula CHR₁₉ or a group of formula NR₂₀ ;

R₁₃ is hydrogen or loweralkyl;

R₁₄ is hydrogen, loweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl,or a group of formula HOCH₂ CH(OH)CH₂ ;

R₁₅ is hydrogen, loweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, agroup of formula ##STR3## wherein s is 1 or 2, a group of formula##STR4## a group of formula HOCH₂ CH(OH)CH₂, or a group of formula(CH₂)_(t) NR₂₁ R₂₂ wherein t is an integer from 2 to 6;

R₁₇ and R₁₈ are the same or different and each is loweralkyl; or

R₁₇ and R₁₈ taken together with the nitrogen atom to which they areattached form a group of formula ##STR5## wherein Y is O or S; R₁₉ ishydrogen, loweralkyl or OR₂₃ ;

R₂₀ is loweralkyl;

R₂₁ and R₂₂ are the same or different and each is loweralkyl; or

R₂₁ and R₂₂ taken together with the nitrogen atom to which they areattached form a group of formula ##STR6## wherein X is as above; R₂₃ ishydrogen or COR₂₄ ;

R₂₄ is loweralkyl; and

the optical and geometric isomers thereof, or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to compounds of formula II ##STR7##wherein R₆, R₇, R₁₇ and R₁₈ are as hereinbeforedefined, which are usefulas intermediates in the preparation of the forskolin derivatives of thepresent invention. Preferably, R₁₇ and R₁₈ are methyl.

Subgeneric to the forskolin derivatives of the present invention arecompounds of formula I wherein:

(a) R₁ and R₉ taken together form a group of the formula CHNR₁₇ R₁₈where R₁₇ and R₁₈ are the same or different and each is loweralkyl,preferably methyl;

(b) R₁ is hydrogen;

(c) R₆ is hydrogen;

(d) R₁, R₆ and R₉ are hydrogen;

(e) R₆ is CONR₁₆ (CH₂)_(u) NR₂₅ R₂₆ wherein R₁₆ is hydrogen orloweralkyl, preferably hydrogen, and R₂₅ and R₂₆ are the same ordifferent and each is hydrogen or loweralkyl, preferably methyl, and uis an integer from 2 to 5, preferably 2 or 3;

(f) R₁ and R₉ are hydrogen and R₆ is CONR₁₆ (CH₂)_(u) NR₂₅ R₂₆ whereinR₁₆ is hydrogen or loweralkyl, preferably hydrogen, and R₂₅ and R₂₆ arethe same or different and each is hydrogen or lower alkyl, preferablymethyl, and u is an integer from 2 to 5, preferably 2 or 3;

(g) R₇ is phenyl which is mono- or poly-substituted by nitro, an examplebeing para-nitrophenyl;

(h) R₇ is pyridinyl, an example being 2-pyridinyl, or pyridinyl which ismono- or poly-substituted by halogen, an example being2-(6-fluoropyridin-2-yl);

(i) R₇ is pyrimidinyl, an example being pyrimidin-2-yl, or pyrimidinylwhich is mono- or poly-substituted by halogen, an example being2-chloropyrimidin-4-yl; and

(j) R₇ is purinyl or purinyl which is mono- or poly-substituted byloweralkyl, preferably methyl, an example being 1-methylpurin-6-yl.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 8 carbon atoms such asmethyl, ethyl, 1-propyl, 2-propyl, 2-methylpropyl, 1-pentyl, 2-pentyl,3-hexyl, 4-heptyl, 2-octyl, and the like. The term "alkenyl" refers to astraight or branched chain hydrocarbon radical containing one or moredouble bonds and having 1 to 8 carbon atoms such as propenyl, pentenyl,hexenyl, and the like. The term "alkanol" refers to a compound formed bya combination of an alkyl group and a hydroxy radical and includes, forexample, methanol, ethanol, 1- and 2-propanol, 1, 2-dimethylethanol,hexanol, octanol, and the like. The term "alkoxy" refers to a compoundformed by a combination of an alkyl group and a hydroxy group andincludes, for example, methoxy, ethoxy, propoxy, butoxy, and the like.The term "alkoxide" refers to a compound formed by the combination of analkoxy group and a metal and includes, for example, potassiumt-butoxide. The term "alkanoic acid" refers to a compound formed bycombination of a carboxyl group with a hydrogen atom or alkyl group.Examples of alkanoic acids are formic acid, acetic acid, propanoic acid,2,2-dimethylacetic acid, hexanoic acid and the like. The term "halogen"refers to a member of the family consisting of fluorine, chlorine,bromine or iodine. The term "lower" as applied to any of theaforementioned groups refers to a group having a carbon skeletoncontaining up to and including six carbon atoms. The term "aryl" refersto an organic radical derived from an aromatic hydrocarbon by theremoval of one hydrogen atom, such as, e.g., phenyl, tolyl, salicyl,napthyl, etc.

In the formulas presented herein, the various substituents areillustrated as joined to the forskolin nucleus by one of two notations:a solid line (--) indicating a substituent which is in the β-orientation(i.e., above the plane of the molecule) and a broken line (---)indicating a substituent which is in the α-orientation (i.e., below theplane of the molecule). The formulas have all been drawn to show thecompounds in their absolute stereochemical configuration. Inasmuch asthe starting materials having a forskolin nucleus are naturallyoccurring or are derived from naturally occurring materials, they, aswell as the final products, have a forskolin nucleus existing in thesingle absolute configuration depicted herein. The processess of thepresent invention, however, are intended to apply as well to thesynthesis of forskolin derivatives of the racemic series.

In addition to the optical centers of the forskolin nucleus, thesubstituents thereon may also contain chiral centers contributing to theoptical properties of the compounds of the present invention andproviding a means for the resolution thereof by conventional methods,for example, by the use of optically active acids. The present inventioncomprehends all optical isomers and racemic forms of the compounds ofthe present invention, where such compounds have chiral centers inaddition to those of the labdane nucleus.

The novel forskolin derivatives of the present invention are synthesizedby the representative processes illustrated in Reaction Schemes A and Bimmediately preceding the claims.

Referring to Scheme A, compounds of formula 3 are prepared by reacting acompound of formula 1 (e.g., 7-desacetylforskolin 1,9-dimethylformamideacetal) with a compound of formula R₇ -Hal, wherein R₇ is ashereinbeforedefined and Hal is halogen, to provide arylether 2 which isthen hydrolyzed by treatment with a mixture of an alkanol and water or amixture of an alkanol, water and acetic acid to afford compound 3.

The arylation of compound 1 is readily accomplished by treating compound1 with an aryl- or heteroaryl halide in the presence of a metalalkoxide. Aryl- or heteroaryl halides used in accordance with theinvention have the formula R₇ -Hal, wherein R₇ is as hereinbeforedefinedand Hal is halogen, and include, for example, 2-fluoropyridine,2-chloropyrimidine, 2,6-difluoropyridine, 1-fluoro-4-nitrobenzene,2,4-dinitrofluorobenzene, 2,4-dichloropyrimidine and6-chloro-1-methyl-purine. The arylation is conducted in a number ofsolvents well known in the art. Of these solvents, tetrahydrofuran ispreferred. Metal alkoxides used in accordance with the invention includea number of substances well known in the art, potassium t-butoxide beingpreferred. While the temperature at which the arylation is performed isnot narrowly critical, it is preferred to conduct the reaction at atemperature ranging from about -20° to 100° C. It is most preferred toperform the arylation at a temperature ranging from about 0° to 50° C.

The deacetalation is effected by hydrolyzing compound 2 with a mixtureof an alkanol and water or a mixture of an alkanol, water and aceticacid. Among the alkanols, there may be mentioned, for example, methanol,ethanol and propanol. Methanol is the preferred alkanol. While theproportion of alkanol to water is not narrowly critical, a proportion of3:1 is preferred. Deacetalation proceeds at a temperature ranging fromabout 0° to 100° C. with a temperature ranging from about 60°-70° C.being preferred.

Referring to Scheme B, compounds of formula 6 are prepared in the samemanner as compounds of formula 3 except that instead of using a compoundof formula 1, a compound of formula 4 is used wherein R₆ is ashereinbeforedefined.

The starting materials for the processes of the present invention asshown in Scheme A, i.e., forskolin derivatives of formula 1, aredescribed in U.S. Pat. No. 4,639,443, issued Jan. 27, 1987, thedisclosure of which is incorporated herein by reference. The startingmaterials for the processes of the present invention as shown in SchemeB, i.e., forskolin derivatives of formula 4, are described in U.S. Ser.No. 137,998, filed Dec. 28, 1987, the disclosure of which isincorporated herein by reference.

U.S. Pat. Nos. 4,639,446, issued Jan. 27, 1987, 4,666,904, issued May19, 1987, 4,672,115, issued Jun. 9, 1987, 4,673,752, issued Jun. 16,1987, and 4,677,103, issued Jun. 30, 1987, the disclosure of each ofwhich patents is incorporated herein by reference, disclose a variety ofmethods which can be used for further derivatization of forskolincompounds 3 and 6 of the present invention at the 1-position. Thedisclosure of U.S. Ser. No. 137,998 also discloses methods which can beused for further derivatization of compounds 3 and 6 of the presentinvention at the 1-position. In particular, these methods can be used toprepare compounds of the invention wherein R₁ is R₃ R₄ R₅ Si, R₈ CO andR₁₀ P₁₁ N(CHR₁₂)_(n) CO wherein R₃, R₄, R₅, R₈, R₁₀, R₁₁ and n arehereinbeforedefined. S. V. Bhat et al., "The Antihypertensive andPositive Inotropic Diterpene Forskolin: Effects of StructuralModifications on Its Activity", J. Med. Chem., 26, 487-493 (1983) and S.V. Bhat et al., "Reactions of Forskolin, A Biologically ActiveDiterpenoid from Coleus forskolii", J. Chem. Soc., Perkin I, 767-771(1982) disclose methods for derivatization of compounds 3 and 6 of thepresent invention at the 1-position wherein R₁ is loweralkyl orarylloweralkyl.

The aryl and heteroaryl ethers of desacetylforskolin of the presentinvention are useful in the treatment of cardiac failure by virtue oftheir ability to elicit a positive inotropic effect as evidenced by anincrease in contractile force in an isolated guinea pig atria assaywhich is performed as follows:

Male guinea pigs weighing 200-300 grams are stunned with a blow to theback of the head. The heart is rapidly removed and placed in a petridish containing Kreb's solution. The ventricle is separated from theatria, the atria are sectioned in the right and left atria, and double-Osilk ligatures are tied to the apex of the left atrium. The atrium isfixed to a pair of platinum plate electrodes and suspended in a 20 mltissue bath containing Kreb's solution aerated with 95% oxygen-5% carbondioxide at 37° C. One end of the atrium is fixed to a hook in theelectrode and the other end is connected to a Grass FTO3 forcedisplacement transducer. Resting tension and stabilization time are thesame as described above. The atrium is stimulated at 3 Hz, 0.5 msecduration at supramaximal voltage (constant current) via a Grass S88stimulator and constant current unit. Force of contraction iscontinuously displaced on a Gould recorder. Test drug is prepared as insection A and is added to the tissue baths in the same fashion. Changein contractile force from baseline is determined for each concentration,and the change in contractile force (g) is plotted against accumulateddrug concentration (ug/ml). The activity of the test drug, i.e., theincrease in contractile force (g) from the stabilized force expressed asthe percentage change at a given concentration is determinedgraphically, as is the ED₅₀ -value, i.e., the extrapolated dose (μg/ml)which increases the contractile force by 50% over the stabilized rate.

Results obtained in this assay for representative compounds of theinvention and a reference compound are presented in the Table.

                  TABLE                                                           ______________________________________                                                               INOTROPIC ACTIVITY                                     COM-    CONCENTRATION  (% Change of                                           POUND   (μg/ml)     Contractile Force)                                     ______________________________________                                        A.sup.1 0.009.sup.2    50                                                     B.sup.3 0.01.sup.2     50                                                     C.sup.4,5                                                                             0.073.sup.2    50                                                     ______________________________________                                         .sup.1 7Desacetyl-6-(2-dimethylaminoethylaminocarbonyl)-7-(pyridin-2-yl)      forskolin hydrochloride hydrate                                               .sup.2 Extrapolated ED.sub.50 value                                           .sup.3 7Desacetyl-7-(pyrimidin-2-yl) forskolin                                .sup.4 Forskolin                                                              .sup.5 Reference Compound                                                

Cardiac failure treatment is achieved when the forskolin derivatives ofthe present invention are administered to a subject requiring suchtreatment as an effective oral, parenteral or intravenous dose of fromabout 0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 25 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosage set forth herein are exemplary only and that they do not, to anyextent, limit the scope of practice of the invention.

Compounds of the present invention are also useful for the treatment ofmemory loss, hypertension, bronchial asthma, glaucoma and psoriasis.

Compounds of the present invention include:

7-desacetyl-6-(3-dimethylaminopropylaminocarbonyl)(pyrimidin-yl)forskolin;

7-desacetyl-6-(4-dimethylaminobutylaminocarbonyl)(pyrimidin-2-yl)forskolin;

7-desacetyl-7-[2-(3-dimethylaminopropylamino)pyrimidin-4-yl]forskolin

7-desacetyl-7-[2-(2-dimethylaminoethylamino)pyrimidin-4-yl]forskolin

6-acetyl-7-desacetyl-7-(pyrimidin-2-yl)forskolin;

7-desacetyl-7-(2-chloropyrimidin-4-yl)forskolin;

7-desacetyl-7-(pyrimidin-2-yl)forskolin-6-methylether;

7-desacetyl-6-(methylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin;

7-desacetyl-7-(pyrimidin-4-yl)forskolin;

7-desacetyl-7-(2-hydroxypyrimidin-4-yl)forskolin;

7-desacetyl-7-(4-aminophenyl)forskolin;

7-desacetyl-6,7-bis(4-aminophenyl)forskolin;

7-desacetyl-7-(4-dimethylaminophenyl)forskolin;

7-desacetyl-6-(3-aminopropylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin;

7-desacetyl-6-(2-aminoethylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin;

7-desacetyl-7-(2-aminophenyl)forskolin; and

7-desacetyl-6-(3-dimethylaminopropylaminocarbonyl)-7-(pyridin-2-yl)forskolin.

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to material of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit,such as, for example, coatings. Thus tablets or pills may be coated withsugar, shellac or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 5% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.001 to 10 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationscan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees Centigrade.

EXAMPLE 1 Preparation of 7-Desacetyl-7-(pyridin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 1.00 g (2.36 mmol) of 7-desacetylforskolin1,9-dimethylformamide acetal in 10 ml of dry tetrahydrofuran was added250 mg (2.23 mmol) of potassium t-butoxide. To the suspension was addedan additional 20 ml of tetrahydrofuran followed by 0.20 ml (0.23 g, 2.33mmol) of 2-fluroropyridine and the suspension was then stirred at roomtemperature under nitrogen for 0.5 hr and at 60°-65° for 2.5 hr. Thesolution was cooled to room temperature, 25 mg (0.22 mmol) of potassiumt-butoxide was added followed by 0.05 ml (0.057 g, 0.57 mmol) of2-fluororopyridine and the resulting solution was stirred at 60°-65° for0.5 h and allowed to cool to room temperature. The solution was pouredinto ice water/ether, extracted twice with ether, washed with water,saturated sodium chloride, dried over sodium sulfate and filtered.Evaporation of the solvent provided an oil which was dissolved in aminimum volume of ethyl acetate and flash chromatographed on silica gel,eluting with 25% ethyl acetate/hexane. The product-containing fractionswere combined and concentrated to a white solid which was recrystallizedfrom cyclohexane to provide 0.536 (1.07 mmol, 45.3%) of colorlessneedles of 7-desacetyl-7-(pyrid-2-yl)forskolin 1,9-dimethylformamideacetal, mp 151°-164°. The material appeared pure by thin layerchromatography on silica gel: 25% ethyl acetate/hexane, R_(f) =0.15; 30%acetone/hexane, R_(f) =0.4. IR(CHCl₃), NMR(CDCl₃) and mass spectra (MH⁺=501) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₈ H₄₀ N₂ O₆ : 67.17% C, 8.05% H, 5.60% N.Found: 67.61% C, 8.11% H, 5.60% N.

EXAMPLE 2 Preparation of 7-Desacetyl-7-(pyridin-2-yl)forskolin

A suspension of 1.0 g (2.0 mmol) of7-desacetyl-7-(pyridin-2-yl)forskolin 1,9-dimethylformamide acetal(prepared as described in Example 1) in 50 ml of 3/1 methanol/water wasstirred at 60°-70° for 40 hr. The solution was allowed to cool to roomtemperature and concentrated to an oil. The oil was dissolved in ethylacetate and flash chromatographed on silica gel, eluting with 25% ethylacetate/hexanes. The product-containing fractions were combined andconcentrated to an oil which was recrystallized from ethylacetate/hexanes to provide 0.372 g (0.832 mmol, 41.6%) of 7-desacetyl148°-151°. The material appeared pure by thin layer chromatography onsilica gel: 25% ethyl acetate/hexane, R_(f) =0.14; 2% methanoldichloromethane R_(f) =0.27. IR(CHCl₃), NMR(CDCl₃) and mass spectra (MH⁺=446) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₅ H₃₅ NO₆ : 67.39% C, 7.92% H, 3.14% N.Found: 67.52% C, 7.90% H, 3.11% N.

EXAMPLE 3 Preparation of 7-Desacetyl-7-(6-fluoropyridin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 5.0 g (11.8 mmol) of 7-desacetylforskolin1,9-dimethyformamide acetal in 100 ml of dry tetrahydrofuran undernitrogen was added 1.33 g (11.9 mmol) of potassium t-butoxide. Thesuspension was stirred for one min under nitrogen and 1.28 ml (14.1mmol) of 2,6-difluoropyridine was added. The suspension graduallydissolved over 45 min after which the solution was stirred for anadditional 15 min, and then poured into ice/water/ethyl acetate. To themixture was then added saturated sodium chloride, and the organic layerwas separated, dried over sodium sulfate, filtered and concentrated toan oil. The oil was purified by flash chromatography on silica gel,eluting with 30% ethyl acetate/hexanes. The product-containing fractionswere combined and concentrated to provide, after recrystallization fromcyclohexane/ethyl acetate, 2.19 g (4.22 mmol, 35.8%) of7-desacetyl-7-6-fluoropyridin-2-yl)forskolin 1,9-dimethylformamideacetal, m.p. 178-181. The material appeared pure by thin layerchromatography on silica gel: 20% ethyl acetate/hexanes, R_(f) =0.11; 1%methanol/dichloromethane, R_(f) =0.12. IR(CHCl₃), NMR(CDCl₃) and massspectra (MH⁺ =519) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₈ H₃₉ FN₂ O₆ : 64.85% C, 7.58% H, 5.40% N.Found: 65.07% C, 7.55% H, 5.41% N.

EXAMPLE 4 Preparation of 7-Desacetyl-7-(6-fluoropyridin-2-yl)forskolin

A solution of 1.2 g (2.31 mmol) of7-desacetyl-7-(6-fluoropyridin-2-yl)forskolin 1,9-dimethylformamideacetal (prepared as described in Example 3) in 60 ml methanol and 20 mlof water was stirred at 60°-70° for 72 hr. The solution was allowed tocool to room temperature and concentrated to an oil. The oil wasdissolved in ethyl acetate, dried over sodium sulfate, filtered andagain concentrated to an oil. The material was dissolved in a minimumvolume of ethyl acetate and flash chromatographed on silica gel, elutingwith 20% ethyl acetate/hexanes followed by 30% ethyl acetate/hexanes.The product-containing fractions were combined and concentrated to anoil which was crystallized from cyclohexane/ethyl acetate to provide, intwo crops, 0.69 g (1.49 mmol, 64.5%) of7-desacetyl-7-(6-fluoropyridin-2-yl)forskolin, mp 166°-168°. Thematerial appeared pure by thin layer chromatography on silica gel: 30%ethyl acetate/hexanes, R_(f) =0.17; 2% methanol/dichloromethane, R_(f)=0.2. IR(CHCl₃), NMR(CDCl₃) and mass spectra (MH⁺ =464) were consistentwith the assigned structure.

ANALYSIS: Calculated for C₂₅ H₃₄ FNO₆ : 64.78% C, 7.39% H, 3.02% N.Found: 64.56% C, 7.30% H, 3.05% N.

EXAMPLE 5 Preparation of 7-Desacetyl-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 5.0 g (11.8 mmol) of 7-desacetylforskolin1,9-dimethylformamide acetal in 100 ml of dry tetrahydrofuran was added1.33 g (11.6 mmol) of potassium t-butoxide. The suspension was stirredat room temperature for several minutes and 1.6 g (14.0 mmol) of2-chloropyrimidine was added. The mixture was stirred 3 hr at roomtemperature, poured into ice/water/dichloromethane and the organic layerwas separated, washed with sodium chloride and concentrated in vacuo.The residue was dissolved in a minimum volume of ethyl acetate and flashchromatographed on silica gel, eluting with 30% ethyl acetate/hexane.The fractions were combined and concentrated in vacuo, leaving a solidwhich was recrystallized from cyclohexane/ethyl acetate to provide 2.00g (3.99 mmol, 33.8%) of 7-desacetyl-7-(pyrimidin-2-yl)forskolin, mp200°-208°. The material appeared pure by thin layer chromatography onsilica gel: 30% ethyl acetate/hexanes, R_(f) =0.14; 5%methanol/dichloromethane, R_(f) =0.2. IR(CHCl₃), NMR (CDCl₃) and massspectra (MH⁺ =502) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₇ H₃₉ N₃ O₆ : 64.65% C, 7.84% H, 8.38% N.Found: 64.67% C, 7.85% H, 8.31% N.

EXAMPLE 6 Preparation of 7-Desacetyl-7-(pyrimidin-2-yl)forskolin

A solution of 1.0 g (1.99 mmol) of7-desacetyl-7-(pyrimidin-2-yl)forskolin 1,9-dimethylformamide acetal(prepared as described in Example 5) was dissolved in a solution ofmethanol/water (3/1) and stirred at 50°-60° for 72 hr. The solution wasallowed to cool to room temperature and was concentrated to a viscousoil. The oil was dissolved in ethyl acetate and flash chromatographed onsilica gel, eluting with 30% ethyl acetate/hexanes. Theproduct-containing fractions were combined and concentrated to provide awhite solid. The solid was dried under vacuum to provide 0.69 g (1.55mol, 77.9%) of 7-desacetyl-7-(pyrimidin-2-yl)forskolin mp 194-198. Thematerial appeared pure by thin layer chromatography on silica gel: 1/1ethyl acetate/hexanes, R_(f) =0.29; 5% methanol/dichloromethane, R_(f)=0.18. IR(CHCl₃), NMR (CDCl₃) and mass spectra (MH+=447) were consistentwith the assigned structure.

ANALYSIS: Calculated for C₂₄ H₃₄ N₂ O₆ : 64.55% C, 7.67% H, 6.28% N.Found: 64.30% C, 7.64% H, 6.18% N.

EXAMPLE 7 Preparation of 7-(2-chloropyrimidin-4-yl)-7-desacetylforskolin1,9-dimethylformamide acetal

To a stirred solution of 10 g (23.6 mmol) of 7-desacetylforskolin1,9-dimethylformamide acetal and 10 g (67.1 mmol) 2,4-dichloropyrimidinein 200 ml of dry tetrahydrofuran in an ice bath was added portion-wiseover 10 min 2.65 g (23.7 mmol) of potassium t-butoxide. The mixture wasstirred for 0.5 hr, poured into ice/sodium bicarbonate and thenextracted with ether. The ether extracts were combined, washed withwater, brine, dried over sodium sulfate, filtered and concentrated to anoil. The oil dried by twice azeotroping with toluene on a rotaryevaporator. The residual oil was dissolved in 200 ml of drytetrahydrofuran and the resulting solution was cooled in an ice bath and2.5 g (22.3 mmol) of potassium t-butoxide followed by 3.5 g (23.5 mmol)of 2,4-dichloropyrimidine were added. The solution was stirred at 0° to5° for 15 min and worked up as above to provide an oil. The oil waspurified by flash chromatography on silica gel, eluting with 10%acetone/hexanes followed by 15% acetone/hexanes to provide 5.66 g (10.6mmol, 44.9%) of a which was recrystallized from cyclohexane to providesolid 7-(2-chloropyrimidin-4-yl) 7-desacetylforskolin1,9-dimethylformamide acetal, mp 155°-164°. The material appeared pureby thin layer chromotography on silica gel: 30% acetone/hexanes, R_(f)=0.22; 1/1 ethyl acetate/hexanes, R_(f) =0.50. IR(CHCl₃), NMR(CDCl₃) andmass spectra (MH⁺ =536) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₇ H₃₈ ClN₃ O₈ : 60.60% C 7.15% H 7.84% N.Found: 60.56% C 7.26% H 7.83% N.

EXAMPLE 8 Preparation of 7-Desacetyl-7-(1-methylpurin-6-yl)forskolin

To a stirred solution of 7-desacetylforskolin 1,9-dimethylformamideacetal (1.5 g, 3.5 mmol) in 30 ml of tetrahydrofuran was added potassiumt-butoxide (0.47 g, 4.2 mmol). After stirring for 15 min,6-chloro-1-methylpurine (0.705 g, 4.2 mmol) was added in one portion.The reaction was quenched with water after 2 hr and extracted withmethylene chloride (2×50 ml). The extracts were dried over sodiumsulfate and concentrated. The residue was purified by chromatography onsilica gel, eluting with hexane/acetone (1:1). The product-containingfractions were combined and concentrated and the resulting residue wascrystallized from cyclohexane/ethyl acetate to give (0.9 gram, 46%) of7-desacetyl-7-(1-methylpurin-6-yl)forskolin 1,9-dimethylformamideacetal. The 1,9-dimethylformamide acetal (550 mg, 0.99 mmol) was heatedat 60° in 10/3 methanol/water for 48 hr. The mixture was allowed to cooland extracted with methylene chloride (2×50 ml). The extracts were driedover sodium sulfate and concentrated to give an off-white solid. Thesolid was purified by flash chromatography, eluting with 5%methanol/methylene chloride and the product-containing fractions werecollected, combined, concentrated and the residue was crystallized fromhexane/ethyl acetate to provide 250 mg (50.5%) of7-desacetyl-7-(1-methylpurin-6-yl)forskolin, mp 183°. The materialappeared pure by thin layer chromatography on silica gel: 5%methanol/methylene chloride, R_(f) =0.22; hexane/acetone (1:1), R_(f)=0.27. IR(KBr), NMR(DMSO), and mass spectra (MH.sup. + =551) wereconsistent with the assigned structure.

ANALYSIS: Calculated for C₂₆ H₃₆ N₄ O₆ : 62.38% C, 7.25% H, 11.19% N.Found: 61.75% C, 7.31% H, 11.11% N.

EXAMPLE 9 Preparation of 7-Desacetyl-7-(4-nitrophenyl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 7-desacetylforskolin 1,9-dimethylformamideacetal (5.0 g, 11.5 mmol) and 1-fluoro-4-nitrobenzene (1.4 g, 13.5 mmol)in 20 ml of tetrahydrofuran was added potassium t-butoxide (1.5 g, 13.5mmol) in small portions. The addition of base was carried out over aperiod of 3 hr with the reaction being monitored closely by thin layerchromatography. The reaction was quenched with cold water and extractedwith methylene chloride (3×100 ml). The methylene chloride extracts weredried over sodium sulfate and concentrated to give an oil which waspurified by flash chromatography on silica gel, eluting with (2:1)hexane/ethyl acetate. The product containing fractions were concentratedto give 1.7 g of 7-desacetyl-7-(4-nitrophenyl) forskolin1,9-dimethylformamide acetal as an amorphous material. The materialappeared pure by thin layer chromatography on silica gel: (2:1)hexane/ethyl acetate, R_(f) =0.42; 1% methanol/methylene chloride, R_(f)=0.17. NMR (CDCl₃) IR(CHCl₃) and mass spectra (MH⁺ =545) were consistentwith the assigned structure.

ANALYSIS: Calculated for C₂₉ H₄₀ N₂ O₈ : 63.95% C, 7.40% H, 5.14% N.Found: 64.29% C, 7.35% H, 4.95% N.

EXAMPLE 10 Preparation of 7-Desacetyl-7-(2,4-dinitrophenyl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 7-desacetylforskolin 1,9-dimethylformamideacetal (5.0 g, 11.5 mmol) and 2,4-dinitrofluorobenzene (2.5 g, 13.5mmol) in 20 ml of tetrahydrofuran was added potassium t-butoxide (1.5 g,13.5 mmol) in small portions. The addition of base was carried out overa period of 4 hr with the reaction being monitored closely by thin layerchromatography. The reaction was quenched with cold water and extractedwith methylene chloride (3×100 ml). The methylene chloride extracts weredried over sodium sulfate and concentrated to an oil which was purifiedby flash chromatography on silica gel, eluting with (3:1) hexane/ethylacetate. The product-containing fractions were concentrated to give 2.9g of 7-desacetyl-7-(2,4-dinitrophenyl) forskolin 1,9-dimethylformamideacetal. The amorphous material appeared pure by thin layerchromatography on silica gel: (2:1) hexane/ethyl acetate, R_(f) =0.38;1% methanol/methylene chloride, R_(f) =0.25. NMR (CDCl₃), IR (CHCl₃) andmass spectra (MH⁺ =590) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₉ H₃₉ N₃ O₁₀ : 59.07% C, 6.67% H, 7.13% N.Found: 59.07% C, 6.76% H, 6.96% N.

EXAMPLE 11 Preparation of 7-Desacetyl methylpurin-6-yl) forskolin 1,9dimethylformamide acetal

To a stirred solution of 1.5 g (3.5 mmol) of 7-desacetylforskolin1,9-dimethylformamide acetal in 30 ml dry tetrahydrofuran was added 0.47g (4.2 mmol) of potassium t-butoxide. The mixture was allowed to stirfor 15 min and then 0.71 g (4.2 mmol) of 6-chloro-1-methylpurine wasadded and stirring was continued for 2 hr. The reaction mixture wasquenched with water and then extracted with methylene chloride. Theextracts were combined, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel, eluting with 1:1 acetone: hexane. Product-containingfractions were combined and concentrated to give 1.5 g of an amorphoussolid. The solid was crystallized from cyclohexane/ethyl acetate to give0.9 g (77%) of 7-desacetyl-7-(1-methylpurin-6-yl) forskolin 1,9dimethylformamide acetal, mp 167°. NMR indicated the presence of acompound with the assigned structure as well as a trace of a sideproduct.

ANALYSIS: Calculated for C₂₉ H₄₁ N₅ O₆ : 62.67% C, 7.45% H, 12.60% N.Found: 60.37% C, 6.91% H, 14.44% N.

EXAMPLE 12 Preparation of7-Desacetyl-6-(2-dimethylaminoethyl)aminocarbonyl)-7-(pyridin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 1.50 g (2.79 mmol) of7-desacetyl-6-(2-dimethylaminoethylaminocarbonyl)forskolin1,9-dimethylformamide acetal in 25 ml of tetrahydrofuran was added 0.313g (2.79 mmol) of potassium t-butoxide. The suspension was stirred atroom temperature for 2-3 min after which 0.36 ml (4.19 mmol) of2-fluoropyridine was added. The mixture was heated to 70° under nitrogenand subsequently stirred for 20 min. To the mixture was added anadditional 0.25 ml (2.91 mmol) of 2-fluoropyridine, and the mixture wassubsequently stirred for 10 min. The solution was allowed to cool toroom temperature, poured into ice/water/sodium bicarbonate/ethyl acetateand the organic layer was separated, washed with saturated sodiumchloride, dried over sodium sulfate, filtered and concentrated to anoil. The oil was dissolved in a minimum volume of 1/1 acetone/hexane andflash chromatographed on silica gel, eluting with 1/1 ethylacetate/hexane, followed by 60% ethyl acetate/hexane. The pureproduct-containing fractions were combined and concentrated to provide,after drying for 2 hr at 110°, 481 mg (0.782 mmol, 28%) of7-desacetyl-6-(2-(dimethylamino)ethylaminocarbonyl)-7-(pyridin-2-yl)forskolin1,9-dimethylformamide acetal, as an oil. The material appeared pure bythin layer chromatography on silica gel: 1/1 acetone/hexane, R_(f) =0.1;10% methanol/dichloromethane, R_(f) =0.1. IR(CHCl₃), NMR(CDCl₃) and massspectra (MH⁺ =615) were consistent with the assigned structure.

ANALYSIS: Calculated for C₃₃ H₅₀ N₄ O₇ : 64.47% C, 8.20% H, 9.11% N.Found: 63.99% C, 8.11% H, 7.91% N.

EXAMPLE 13 Preparation of7-Desacetyl-6-((2-dimethylamino)ethylaminocarbonyl)-7-(pyridin-2-yl)forskolinhydrochloride hydrate

7-Desacetyl-6-((2-dimethylamino)ethylaminocarbonyl)-7-(pyridin-2-yl)forskolin1,9-dimethylformamide acetal (prepared as described in Example 12) (450mg, 0.804 mmol) was dissolved in a minimum volume of methanol and thesolution diluted with 50 ml of 3/1 methanol/water. The solution wasstirred for 18 hr under nitrogen at 60°-65°, and subseqently at 75°-80°for 6 hr. The solution was allowed to cool to room temperature andconcentrated to provide a white solid (0.395 g). The solid wasrecrystallized from 95% ethanol (two crops), washed with hot water anddried under high vacuum at 80°. The dried white solid was dissolved inmethanol and treated with ethereal hydrogen chloride until just acidic.The solvent was evaporated under high vacuum and the residue trituratedwith ether. The resulting white solid was dried at 110° for 2 hr. toprovide 143 mg (0.233 mmol, 29% of7-desacetyl-6-(2-dimethylaminoethylaminocarbonyl)-7-(pyridin-2-yl)forskolin hydrochloride hydrate, mp 175°-195°. The materialappeared pure by thin layer chromatography on silica gel: 10%methanaol/dichloromethane, R_(f) =0.1; 2/1 acetone/hexane, R_(f) =0.11.IR(KBr), NMR(DMSO-d₆) and mass spectra (MH⁺ =560) were consistent withthe assigned spectra.

ANALYSIS: Calculated for C₃₀ H₄₈ ClN₃ O₈ : 58.66% C, 7.88% H, 6.84% N.Found: 58.59% C, 7.57% H, 6.65% N.

EXAMPLE 14 Preparation of7-Desacetyl-6-(3-dimethylaminopropylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of 1.0 g (1.8 mmol) of7-desacetyl-6-[(3-dimethylaminopropyl)aminocarbonyl]forskolin1,9-dimethylformamide acetal in 10 ml of tetrahydrofuran was added 244mg (2.1 mmol) of potassium t-butoxide. The suspension was stirred for 20min before the addition of 250 mg (2.1 mmol) of 2-chloropyrimidine. Themixture was stirred overnight, quenched with water (50 ml) and extractedwith methylene chloride (3×50 ml). The extracts were dried over sodiumsulfate and concentrated to an oil which was purified by chromatographyon silica gel, eluting with 30% methanol/methylene chloride. The productcontaining and fractions were collected and the solvent was removed togive 370 mg (33%) of7-desacetyl-6-(3-dimethylaminopropylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin 1,9-dimethylformamide acetal. The material appeared pure bythin layer chromatography on silica gel: 10% methanol/methylenechloride, R_(f) =0.08; 20% methanol/methylene chloride, R_(f) =0.2.IR(CHCl₃), NMR(CDCl₃), and mass spectra (MH⁺ =630) were consistent forthe assigned structure.

ANALYSIS: Calculated for C₃₃ H₅₁ N₅ O₇ : 62.94% C, 8.16% H, 11.12% N.Found: 62.42% C, 8.20% H, 10.80% N.

EXAMPLE 15 Preparation of7-Desacetyl-6-((2-dimethylamino)ethylaminocarbonyl)-7-(pyrimidin-2-yl)forskolinhydrochloride hydrate

A stirred solution of 2.0 g (3.2 mmol) of7-desacetyl-6-(2-dimethylaminoethylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal in 30 ml of methanol and 10 ml of water washeated at 60° for 48 hr. The mixture was allowed to cool to roomtemperature after which 100 ml of methylene chloride and 50 ml of waterwere added. The organic layer was separated, dried over sodium sulfateand the methylene chloride was removed in vacuo. The crude product wascrystallized from methanol/ether to give 1.35 g (74%) of7-desacetyl-6-(2-dimethylaminoethylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin.A portion (350 mg) was dissolved in hot ethanol and ethereal hydrogenchloride was added until the solution became acidic. Concentration andrecrystallization gave the hydrochloride salt, mp 180° (dec.) The freebase of the material appeared pure by thin layer chromatography onsilica gel: 30% methanol/methylene chloride, R_(f) =0.44; 10%methanol/methylene chloride, R_(f) =0.14. NMR(DMSO), IR(KBr) and massspectra (MH⁺ =561) were consistent with the assigned structure.

ANALYSIS: Calculated for C₂₉ H₄₄ N₄ O₇ HCl H₂ O: 56.61% C, 7.71% H,9.10% N. Found: 56.74% C, 7.63% H, 9.00% N.

EXAMPLE 16 Preparation of7-desacetyl-6-(2-dimethylaminoethyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal

To a stirred solution of7-desacetyl-6-(2-dimethylaminoehtyl)aminocarbonylforskolin1,9-dimethylformamide acetal (3.0 g, 5.6 mmol) in dry tetrahydrofuran(30 ml) was added potassium t-butoxide (750 mg, 6.7 mmol) in one portionfollowed, after 15 min, by 2-chloropyrimidine (760 mg, 6.7 mmol). Afterstirring for 2 hr, additional potassium t-butoxide (300 mg) was addedand the reaction was allowed to stir overnight. Ice and water were addedto the reaction mixture followed by methylene chloride (100 ml), thelayers were separated and the aqueous portion was extracted withadditional methylene chloride. The organic layers were combined, driedover sodium sulfate, concentrated and then purified by flashchromatography on silca gel, eluting with 10% methanol/methylenechloride. The product containing fractions were collected and thesolvent removed to give7-desacetyl-6-(2-dimethylaminoethyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal (1.2 g, 35%). The material appeared pure bythin layer chromatography on silica gel: 10% methanol/methylenechloride, R_(f) =0.16; 30% methanol/methylene chloride, R_(f) =0.47.IR(CHCl₃), NMR (CDCl₃) and mass spectra (MH⁺ =615) are consistent withthe assigned structure.

ANALYSIS: Calculated for C₃₂ H₄₉ N₅ O₇ : 62.40% C, 8.03% H, 11.37%.Found: 62.09% C, 8.02% H, 11.27%.

EXAMPLE 17 Preparation of7-desacetyl-6-(3-dimethylaminopropyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin

7-Desacetyl-6-(3-dimethylaminopropyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal (1.0 g, 1.58 mmol) was dissolved inmethanol (100 ml and water (30 ml). The resulting solution was heated at60° C. under nitrogen atmosphere for 3 days. The reaction mixture wasallowed to cool to room temperature and extracted with methylenechloride (100 ml, 50 ml). The extracts were dried over sodium sulfateand the solvent removed to give a white solid which was crystallizedfrom methanol to give7-desacetyl-6-(3-dimethylaminopropyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin(450 mg, 49%). The material appeared pure by thin layer chromatographyon silica gel: R_(f) =0.04, 10% methanol/methylene chloride; R_(f)=0.12, 30% methanol/methylene chloride. NMR(CDCl₃, DMSO) and massspectrum (MH⁺ =575) are consistent with the assigned structure.

ANALYSIS: Calculated For C₃₀ H₄₆ N₄ O₇ : 62.68% C, 8.08% H, 9.74% N.Found: 62.06% C, 8.01% H, 9.07% N. ##STR8##

We claim:
 1. A compound of formulawherein R₁ and R₉ taken together forma group of formula CHNR₁₇ R₁₈ ; R₆ is hydrogen, a group of formula R₁₃CO or a group of formula CONR₁₄ R₁₅ ; R₇ is phenyl, naphthyl, furanyl,oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl orisoquinolinyl, each of which is unsubstituted or mono- orpoly-substituted by loweralkyl, halogen or nitro; R₁₃ is hydrogen orloweralkyl; R₁₄ is hydrogen, loweralkyl, hydroxyloweralkyl,loweralkoxyloweralkyl, or a group of formula HOCH₂ CH(OH)CH₂ ; R₁₅ ishydrogen, loweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, a groupof formula ##STR9## wherein s is 1 or 2, a group of formula ##STR10## agroup of formula HOCH₂ CH(OH)CH₂, or a group of formula (CH₂)_(t) NR₂₁R₂₂ wherein t is an integer from 2 to 6; R₁₇ and R₁₈ are the same ordifferent and each is loweralkyl; R₂₁ and R₂₂ are the same or differentand each is loweralkyl; or R₂₁ and R₂₂ taken together with the nitrogenatom to which they are attached form a group of formula ##STR11##wherein X is CO, O, S, CHR₂₃ or NR₂₄ ; R₂₃ is hydrogen, loweralkyl orOR₂₅ ; R₂₄ is loweralkyl; R₂₅ is hydrogen or COR₂₆ ; R₂₆ is loweralkyl;andthe optical and geometric isomers thereof, or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein:R₆is hydrogen or a group of formula CONR₁₄ (CH₂)_(t) NR₂₁ R₂₂ ; R₇ isphenyl, pyridinyl, pyrimidinyl or purinyl, each of which isunsubstituted or mono- or poly-substituted by loweralkyl, halogen ornitro; R₁₄ is hydrogen or loweralkyl; and R₁₇, R₁₈, R₂₁ and R₂₂ are thesame or not all the same and each is hydrogen or loweralkyl.
 3. Acompound according to claim 1 wherein R₁ and R₉ taken together form agroup of formula CHN(CH₃)₂.
 4. A compound according to claim 3 whereinR₆ is hydrogen.
 5. A compound according to claim 3 wherein R₆ is CONR₁₄(CH₂)_(t) NR₂₁ R₂₂.
 6. A compound according to claim 5 wherein R₆ isCONH(CH₂)_(t) N(CH₃)₂ and t is 2 or
 3. 7. The compound of claim 4 whichis 7-desacetyl-7-(pyridin-2-yl)forskolin 1,9-dimethylformamide acetal.8. The compound of claim 4 which is7-desacetyl-7-(pyrimidin-2-yl)forskolin 1,9-dimethylformamide acetal. 9.The compound of claim 4 which is7-desacetyl-7-(6-fluoropyridin-2-yl)forskolin 1,9-dimethylformamideacetal.
 10. The compound of claim 4 which is7-desacetyl-7-(4-nitrophenyl)forskolin 1,9-dimethylformamide acetal. 11.The compound of claim 4 which is7-desacetyl-7-(2,4-dinitrophenyl)forskolin 1,9-dimethylformamide acetal.12. The compound of claim 4 which is7-desacetyl-7-(1-methylpurin-6-yl)forskolin 1,9-dimethylformamideacetal.
 13. The compound according to claim 4 which is7-desacetyl-6-(3-dimethylaminopropylaminocarbonyl)-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal.
 14. The compound according to claim 5which is7-desacetyl-6-(2-dimethylaminoethylaminocarbonyl)-7-pyridin-2-yl)forskolin1,9-dimethylformamide acetal.
 15. The compound according to claim 5which is 7-(2-chloropyrimidin-4-yl)-7-desacetylforskolin1,9-dimethylformamide acetal.
 16. The compound according to claim 5which is7-desacetyl-6-(2-dimethylaminoethyl)aminocarbonyl-7-(pyrimidin-2-yl)forskolin1,9-dimethylformamide acetal.